1) Field of the Invention
This invention relates to a sustained-release multi-granule tablet useful in the field of therapy. More specifically, this invention is concerned with a tablet of the multiple unit type, in which sustained-release granules are contained as a unit.
2) Description of the Prior Art
Sustained-release tablets are a preparation form that is intended to reduce the sufferance of patients by reducing the frequency of administration and at the same time to improve the usefulness of a drug to the maximum in view of both advantageous effects and side effects of the drug.
A certain type of sustained-release tablets take the form of the so-called multiple unit. Namely, a drug is firstly converted into a sustained-release particulate or granular form by a suitable method. A powdery or particulate substance composed of one or more formulation adjuvants is then mixed. The resulting mixture is finally compression-formed or compressed into desired Weight, shape and size.
In a drug preparation of the multiple unit type, the drug is divided into a number of granules and is released as an active substance at a suitable velocity into the digestion tract so that the imbalance in the absorption of the drug in each patient and among individual patients is minimized to achieve maximum bioavailability. As typical preparation forms, there are known for example spansule-type capsules in each of which micropills are enclosed in a capsule and tablets of the multiple unit type. The present invention relates to the latter preparation form.
The following two problems have been recognized for many years as drawbacks of tablets of the multiple unit type. The problem of variations in quality is mentioned first of all. In the case of compression-forming, it is generally known that inconsistent mixing occurs due to differences in mixing ratio upon mixing operations, segregation caused by differences in granule number or shape among increments, etc. When tablets of the multiple unit type are produced from sustained-release granules, variations arise as to the contents of the sustained-release granules and the associated granules as a formulation aid by their numbers and their mixing ratio.
Regarding the above-mentioned problem, there is a study conducted by Dr. Shigeo Miwa ["Introduction to Chemical Engineering II", Chapter: "Mixing" (Asakura Shoten)]. From a theoretical curve between the numbers of granules of a drug administered and variation coefficients when the mixing proportion of granules containing an active component is varied in various ways, it is indicated that the variation becomes smaller as the proportion of granules containing the active component increases and the number of granules administered increases.
The present inventors have contemplated how to reduce the variations by applying the above theory to a drug preparation of the multiple unit type. If the proportion of granules containing the active component is increased, the granules are however caused to agglomerate together upon their compression forming and the granules hence become difficult to disperse at the time of the disintegration of the tablet, thereby leading to the loss of the inherent function of the multiple unit. If the number of granules is increased on the other hand, another drawback arises that the preparation form becomes greater.
As the second problem, granules undergo deformation or destruction by high-pressure compression at the time of compression-forming so that the sustained-release function of each unit granule is lost. This may be considered as the largest drawback of multiple unit tablets in a certain sense.